Influence of Rheumatoid Factor Levels and TNF Inhibitor Structure on Secondary Nonresponse in Rheumatoid Arthritis Patients

Overview

Journal Front Med (Lausanne)

Specialty General Medicine

Date 2024 Sep 19

PMID 39296891

Authors

Chamaida Plasencia-Rodriguez

Ana Martinez-Feito

Marta Novella-Navarro

Rebeca Perez de Diego

Gema Bonilla

Johanna Elin Gehin

Alejandro Villalba-Yllan

Laura Nuno

Dora Pascual-Salcedo

Pilar Nozal

Mariana Diaz Almiron

Alejandro Balsa

Affiliations

Soon will be listed here.

Abstract

Background: The EXXELERATE study revealed poorer clinical outcomes in patients treated with adalimumab (ADL) and baseline rheumatoid factor (RF) above 203 IU/mL. However, responses were similar in patients treated with certolizumab pegol (CZP) regardless of RF levels.

Objectives: This study investigated the impact of RF levels >203 IU/mL on TNF inhibitors (TNFi) serum levels and the association with secondary nonresponse in RA patients treated with TNFi.

Methods: We performed an observational ambispective study with RA patients treated with infliximab (IFX), ADL, or CZP. Patients were stratified according to baseline RF levels: ≤ or >203 IU/mL. After 6 months, serum drug levels and antidrug antibodies were measured, and reasons for discontinuation were collected.

Results: We included 170 RA patients: 90 (53%) received IFX, 48 (28%) ADL, and 32 (19%) CZP. While CZP serum levels did not differ between RF groups at 6 months ( = 0.6), RF levels >203 IU/mL were linked to lower serum drug levels in patients treated with IFX ( = 0.09) or ADL ( = 0.02). Secondary nonresponse was 3.6 times higher in patients with high versus low RF levels in patients under IFX or ADL. However, the reasons for withdrawal were not affected by RF levels in patients treated with CZP.

Conclusion: Baseline RF above 203 IU/mL is associated with lower serum drug levels and an increased risk of discontinuation due to secondary nonresponse in patients treated with IFX or ADL. In contrast, drug levels and clinical outcomes are not significantly impacted by baseline RF levels in patients under CZP.

References

Tanaka Y . Recent progress in treatments of rheumatoid arthritis: an overview of developments in biologics and small molecules, and remaining unmet needs. Rheumatology (Oxford). 2021; 60(Suppl 6):vi12-vi20. PMC: 8709568. DOI: 10.1093/rheumatology/keab609. View

Berkhout L, Vogelzang E, Hart M, Loeff F, Dijk L, Derksen N . The effect of certolizumab drug concentration and anti-drug antibodies on TNF neutralisation. Clin Exp Rheumatol. 2019; 38(2):306-313. View

Machold K, Stamm T, Nell V, Pflugbeil S, Aletaha D, Steiner G . Very recent onset rheumatoid arthritis: clinical and serological patient characteristics associated with radiographic progression over the first years of disease. Rheumatology (Oxford). 2006; 46(2):342-9. DOI: 10.1093/rheumatology/kel237. View

Bird P, Hall S, Nash P, Connell C, Kwok K, Witcombe D . Treatment outcomes in patients with seropositive versus seronegative rheumatoid arthritis in Phase III randomised clinical trials of tofacitinib. RMD Open. 2019; 5(1):e000742. PMC: 6397430. DOI: 10.1136/rmdopen-2018-000742. View

Salgado E, Maneiro J, Carmona L, Gomez-Reino J . Safety profile of protein kinase inhibitors in rheumatoid arthritis: systematic review and meta-analysis. Ann Rheum Dis. 2013; 73(5):871-82. DOI: 10.1136/annrheumdis-2012-203116. View

Hyrich K, Watson K, Silman A, Symmons D . Predictors of response to anti-TNF-alpha therapy among patients with rheumatoid arthritis: results from the British Society for Rheumatology Biologics Register. Rheumatology (Oxford). 2006; 45(12):1558-65. DOI: 10.1093/rheumatology/kel149. View

Choy E, McKenna F, Vencovsky J, Valente R, Goel N, VanLunen B . Certolizumab pegol plus MTX administered every 4 weeks is effective in patients with RA who are partial responders to MTX. Rheumatology (Oxford). 2012; 51(7):1226-34. DOI: 10.1093/rheumatology/ker519. View

Bos W, Bartelds G, Wolbink G, de Koning M, van de Stadt R, van Schaardenburg D . Differential response of the rheumatoid factor and anticitrullinated protein antibodies during adalimumab treatment in patients with rheumatoid arthritis. J Rheumatol. 2008; 35(10):1972-7. View

Bobbio-Pallavicini F, Caporali R, Alpini C, Moratti R, Montecucco C . Predictive value of antibodies to citrullinated peptides and rheumatoid factors in anti-TNF-alpha treated patients. Ann N Y Acad Sci. 2007; 1109:287-95. DOI: 10.1196/annals.1398.034. View

10.

Kolate A, Baradia D, Patil S, Vhora I, Kore G, Misra A . PEG - a versatile conjugating ligand for drugs and drug delivery systems. J Control Release. 2014; 192:67-81. DOI: 10.1016/j.jconrel.2014.06.046. View

11.

Aletaha D, Neogi T, Silman A, Funovits J, Felson D, Bingham 3rd C . 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum. 2010; 62(9):2569-81. DOI: 10.1002/art.27584. View

12.

Takeuchi T, Miyasaka N, Inoue K, Abe T, Koike T . Impact of trough serum level on radiographic and clinical response to infliximab plus methotrexate in patients with rheumatoid arthritis: results from the RISING study. Mod Rheumatol. 2009; 19(5):478-87. PMC: 2759008. DOI: 10.1007/s10165-009-0195-8. View

13.

Nielsen S, Bojesen S, Schnohr P, Nordestgaard B . Elevated rheumatoid factor and long term risk of rheumatoid arthritis: a prospective cohort study. BMJ. 2012; 345:e5244. PMC: 3435445. DOI: 10.1136/bmj.e5244. View

14.

Wojtal K, Rogler G, Scharl M, Biedermann L, Frei P, Fried M . Fc gamma receptor CD64 modulates the inhibitory activity of infliximab. PLoS One. 2012; 7(8):e43361. PMC: 3427356. DOI: 10.1371/journal.pone.0043361. View

15.

Potter C, Hyrich K, Tracey A, Lunt M, Plant D, Symmons D . Association of rheumatoid factor and anti-cyclic citrullinated peptide positivity, but not carriage of shared epitope or PTPN22 susceptibility variants, with anti-tumour necrosis factor response in rheumatoid arthritis. Ann Rheum Dis. 2008; 68(1):69-74. PMC: 2596303. DOI: 10.1136/ard.2007.084715. View

16.

Nakayama Y, Watanabe R, Murakami K, Murata K, Tanaka M, Ito H . Differential efficacy of TNF inhibitors with or without the immunoglobulin fragment crystallizable (Fc) portion in rheumatoid arthritis: the ANSWER cohort study. Rheumatol Int. 2022; 42(7):1227-1234. DOI: 10.1007/s00296-021-05086-w. View

17.

Ogawa Y, Takahashi N, Kaneko A, Hirano Y, Kanayama Y, Yabe Y . Association between seropositivity and discontinuation of tumor necrosis factor inhibitors due to ineffectiveness in rheumatoid arthritis. Clin Rheumatol. 2019; 38(10):2757-2763. DOI: 10.1007/s10067-019-04626-x. View

18.

Porter C, Armstrong-Fisher S, Kopotsha T, Smith B, Baker T, Kevorkian L . Certolizumab pegol does not bind the neonatal Fc receptor (FcRn): Consequences for FcRn-mediated in vitro transcytosis and ex vivo human placental transfer. J Reprod Immunol. 2016; 116:7-12. DOI: 10.1016/j.jri.2016.04.284. View

19.

Fleischmann R, Vencovsky J, van Vollenhoven R, Borenstein D, Box J, Coteur G . Efficacy and safety of certolizumab pegol monotherapy every 4 weeks in patients with rheumatoid arthritis failing previous disease-modifying antirheumatic therapy: the FAST4WARD study. Ann Rheum Dis. 2008; 68(6):805-11. PMC: 2674555. DOI: 10.1136/ard.2008.099291. View

20.

Levy R, Guzman R, Castaneda-Hernandez G, Martinez-Vazquez M, Damian G, Cara C . Biology of anti-TNF agents in immune-mediated inflammatory diseases: therapeutic implications. Immunotherapy. 2016; 8(12):1427-1436. DOI: 10.2217/imt-2016-0067. View